Drug levels can be maintained above the lower level of the therapeutic plasma concentration for longer periods of time by giving larger doses of conventionally formulated dosage forms. However, it is not a suitable approach to increase dosage as such doses may produce toxic and undesired high drug levels. Alternatively, another approach is to administer a drug at certain intervals of time, resulting in oscillating drug levels, the so-called peak and valley effect. This approach is generally associated with several potential problems, such as a large peak (toxic effect) and valley (non-active drug level) effect, and a lack of patient compliance leading to drug therapy inefficiency or failure. If, however, the plasma concentration is kept constant over the therapeutic level using conventional tablets, an unacceptably high daily dosage is required if the opioid is not administered very frequently.
Controlled release preparations are known which are designed to rapidly release a fraction of a total drug dose. This loading dose is an amount of a drug which will provide a desired pharmacological response as promptly as possible according to the biopharmaceutical properties of the drug. Such formulations which initially release a burst of a therapeutic agent and then release the agent at an essentially constant rate are described in WO 95/14460 published on Jun. 1, 1995. The composition described therein relates to a sustained release opioid formulation comprising a plurality of substrates comprising the active ingredient in a sustained release matrix or coated with a sustained release coating comprising a retardant material. The sustained release beads are then coated with an opioid in immediate release form or, in the case the composition is in the form of a gelatine capsule, the plain opioid is incorporated into the gelatin capsule via inclusion of the sufficient amount of immediate release opioid as a powder or granulated within the capsule. In a further alternative, the gelatine capsule itself is coated with an immediate release layer of the opioid.
A major disadvantage of the above formulation is that the incorporation of the plain opioid in gelatine capsules without a protecting coating on the opioid may easily result in lack of control of the exact dosage, especially if the capsule leaks or the patient breaks the capsule. In addition it is not possible to modify the release in relation to the sustained release fraction, and the only possibility of avoiding toxic plasma concentrations, or controlling the peak plasma concentration, is to decrease the exact amount of opioid of the immediate release portion.
The above-mentioned controlled release preparations are long-acting and release the drug in a sustained manner. However, these types of formulations may result in an undesirable decreased bioavailability, probably because the active ingredient is not released in due time.
Multiple-units formulation techniques according to the invention aim at a modified release of active substance in a predetermined pattern to reduce and delay the peak plasma concentration without affecting the extent of drug availability. The frequency of undesirable side effects may be reduced, and due to the delay in the time it takes to obtain the peak plasma concentration and the prolongation of the time at the therapeutically active plasma concentration, the frequency of the administration may be reduced to a dosage taken only twice or once a day. This also serves to improve patient compliance. A further advantage of the modified release multiple-units dosage form is that high local concentrations of the active substance in the gastrointestinal system are avoided, due to the units being distributed freely throughout the gastrointestinal tract, independent of emptying.
Moreover, patients suffering from chronic pains very often require high daily dosages of analgesic, e.g. about 100 mg of morphine. If such high dosage of an opioid should be given once a day, the release from the dosage form must be safe. The formulation should also be very storage stable because an immediate release due to accidental damaging of e.g. the coating or capsule of a high dosage form may result in undesired high plasma concentrations, so-called dose dumping, which could cause the death of the patient. By use of a coated multiple unit dosage form, the risk of dose dumping due to e.g. rupturing of a coating is reduced because the amount of active ingredient in each coated unit is negligible.
However, a major disadvantage of the once-a-day treatment in the art may be a low peak plasma concentration at the end of the day and thereby the lack of pain relief. As the treatment of pain is a balance of pain relief on the one hand and the risk of side effects on the other hand, e.g. due to accumulation of drug, the dosage interval is generally calculated so that the drug concentration is substantially decreased at the time of intake of the next dosage. Accordingly, the patient will very often suffer from increasing pain before the drug concentration subsequent to the next dosage has reached the therapeutic level. In addition, it should be noted that in the treatment of pain, relatively higher dosages, corresponding to a relatively higher peak concentration, are often needed in case the pain breaks through. Accordingly, a relatively higher initial plasma concentration of analgesic may be necessary compared to the plasma concentration which is capable of maintaining a state of pain relief.
As treatment of chronic pains very often involves a life-long treatment, and thereby involves high cost, once-a-day dosage forms should not imply an expensive and complicated production method, as a higher cost of such a product compared to the cost for the conventional products would indeed interfere with the success of the drug.
However, no oral analgesic pharmaceutical composition has been disclosed which at the same time can be produced in an easy, cheap and reliable manner and which provides a suitable profile for release of active substance resulting in an extended period of action so that pain is both rapidly alleviated after administration and avoided for a period of about 12 to 24 hours.
Therefore, there is a need of a formulation comprising an opioid substance permitting the administration of large as well as small, daily dosages only once or twice a day in a safe and reliable manner, and which is easy to produce, preferably involving conventional production methods and as few product steps as possible. It is also important that an opioid formulation for daily administration comprises the active ingredient in such a way that the formulation has a reliable dissolution rate since unexpected fast dissolution of the opioid could be dangerous for the patient.